Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic review and network meta-analysis including aggregate results from reanalysed individual patient data

Janke, Kirsten; Biester, Katharina; Krause, D.; Richter, Bernd; Schürmann, Christoph; Hirsch, Karin; Hörn, Helmut; Kerekes, Michaela F; Kohlepp, Petra; Wieseler, Beate

doi:10.1136/bmj.m2288

Cited by 39 publications

(30 citation statements)

References 38 publications

(61 reference statements)

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“…Other systematic reviews and network meta-analyses looking at the comparative effectiveness of biological drugs have mainly focused on patients with disease that has failed to respond to methotrexate. 39 Meaning of the study: possible explanations and implications for clinicians and policy makers The primary clinical outcome was CDAI remission at 24 weeks, a more stringent remission criterion than the DAS28 based criterion, which has traditionally been used in many trials. We chose the CDAI because the algorithm does not include acute phase reactants, which are differentially impacted upon by different biological treatments.…”

Section: Strengths and Weaknesses In Relation To Other Studies Discumentioning

confidence: 99%

Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial

Hetland

Haavardsholm

Rudin

et al. 2020

BMJ

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Objective To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. Design Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. Setting Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. Participants Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. Interventions Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. Main outcome measures The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. Results 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval −5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and −0.6% (−10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. Conclusions All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis. Trial registration EudraCT2011-004720-35, NCT01491815 .

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Section: Strengths and Weaknesses In Relation To Other Studies Discumentioning

confidence: 99%

Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial

Hetland

Haavardsholm

Rudin

et al. 2020

BMJ

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“…Due to its lack of trans-placental transport, it has been approved in RA treatment during pregnancy [ 41 , 62 ]. Efficacy of CTZ seems to be comparable to other TNFi in RA treatment, although in the majority of patients neutralizing antibodies were found [ 63 ]. Yet, high concentrations of CTZ in sera (>10 mg/L) were able to sustain a sufficient clinical response in RA treatment [ 64 ].…”

Section: Bdmards Based On Cytokine-targeted Therapymentioning

confidence: 99%

“…Therefore, the presence of neutralizing antibodies could result from high concentrations of CTZ administration. In large cohort studies there were no significant safety issues in RA treatment [ 65 ], although in meta-analysis increased number of serious adverse events (SAE) and infections was observed in the CTZ group in comparison to other TNFi [ 63 ]. As of today, there are no CTZ biosimilar drugs present.…”

Section: Bdmards Based On Cytokine-targeted Therapymentioning

confidence: 99%

Biologic Drugs for Rheumatoid Arthritis in the Context of Biosimilars, Genetics, Epigenetics and COVID-19 Treatment

Bonek

Roszkowski

Massalska

et al. 2021

Cells

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Rheumatoid arthritis (RA) affects around 1.2% of the adult population. RA is one of the main reasons for work disability and premature retirement, thus substantially increasing social and economic burden. Biological disease-modifying antirheumatic drugs (bDMARDs) were shown to be an effective therapy especially in those rheumatoid arthritis (RA) patients, who did not adequately respond to conventional synthetic DMARD therapy. However, despite the proven efficacy, the high cost of the therapy resulted in limitation of the widespread use and unequal access to the care. The introduction of biosimilars, which are much cheaper relative to original drugs, may facilitate the achievement of the therapy by a much broader spectrum of patients. In this review we present the properties of original biologic agents based on cytokine-targeted (blockers of TNF, IL-6, IL-1, GM-CSF) and cell-targeted therapies (aimed to inhibit T cells and B cells properties) as well as biosimilars used in rheumatology. We also analyze the latest update of bDMARDs’ possible influence on DNA methylation, miRNA expression and histone modification in RA patients, what might be the important factors toward precise and personalized RA treatment. In addition, during the COVID-19 outbreak, we discuss the usage of biologicals in context of effective and safe COVID-19 treatment. Therefore, early diagnosing along with therapeutic intervention based on personalized drugs targeting disease-specific genes is still needed to relieve symptoms and to improve the quality of life of RA patients.

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“…The Institute for Quality and Efficiency in Health Care (IQWiG) requested re-analysis of individual participant data from several industry sponsored randomised trials to harmonise patient populations and primary endpoints before findings could be combined in network meta-analyses. 45 Prompt access to comparative data is critical. As there is an ethical imperative for any treatment with promising results to immediately become the new standard of care (as occurred with dexamethasone, and to a lesser extent remdesivir, in patients with severe covid-19), comparative assessments should ideally accompany the publication of individual trial results.…”

Section: Assessing Comparative Effectivenessmentioning

confidence: 99%

“…A recent health technology assessment of biological agents for rheumatoid arthritis in Germany has shown the feasibility of this approach. The Institute for Quality and Efficiency in Health Care (IQWiG) requested re-analysis of individual participant data from several industry sponsored randomised trials to harmonise patient populations and primary endpoints before findings could be combined in network meta-analyses 45…”

Section: Areas For Improvementmentioning

confidence: 99%

Producing and using timely comparative evidence on drugs: lessons from clinical trials for covid-19

Naci

Kesselheim

Røttingen

et al. 2020

BMJ

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Since the early days of the novel coronavirus outbreak, a record number of studies have been launched to test several repurposed and new medicines as potential treatments for covid-19. 1 An analysis by the news organisation STAT identified over 1000 clinical trials registered on ClinicalTrials.gov between January and June 2020. 2 This is a testament to the research and clinical community's commitment to identify effective treatments for covid-19. However, the large volume of studies may paradoxically limit the generation of robust evidence and complicate the formulation of trustworthy guidance and decisions related to drug use if the current research is duplicative and redundant or produces conflicting data. 3-5 Indeed, the multiplicity of research on candidate therapeutics for covid-19 has exposed important flaws and failures in the current evidence ecosystem. 6 7 Crucially, these limitations also affect the full spectrum of research on new health technologies. 8 9 Users of evidence across the healthcare system (patients, clinicians, health technology assessment bodies, guideline developers, payers) need timely data on how different treatments compare with each other in terms of their benefits and harms-their comparative effectiveness. Producing comparative evidence and ensuring its rapid translation into trustworthy guidance requires extensive coordination and collaboration between the researchers conducting clinical trials, those conducting comparative effectiveness assessments, and those producing guidance. 8 9 The experience of covid-19 highlights the difficulties in making comparative assessments and suggests areas for improvement.

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Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic review and network meta-analysis including aggregate results from reanalysed individual patient data

Cited by 39 publications

References 38 publications

Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial

Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial

Biologic Drugs for Rheumatoid Arthritis in the Context of Biosimilars, Genetics, Epigenetics and COVID-19 Treatment

Producing and using timely comparative evidence on drugs: lessons from clinical trials for covid-19

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